This continuing Program Project focuses on the interaction between biomechanical and inflammatory factors in the pathogenesis of osteoarthritis (OA). The project represents a highly interdisciplinary approach to investigate specific biomechanical, molecular, and psychological mechanisms that relate to disease outcome. The focus of the program is the quantitative study of biomarkers of inflammation, pain, and matrix metabolism in four interrelated studies, performed at the in vivo (human and experimental animal) and in vitro levels. In Project 1, we will examine the influence of genetically- or diet-induced obesity on OA in a mouse model, and examine mechanisms involved in the interaction of biomechanical and biochemical factors on regulating cartilage matrix metabolism and biomarkers of OA using in vitro explant model systems. In Project 2, we will design and evaluate a thermally triggered, in situ forming intra-articular drug depot capable of providing long-term release of anti-cytokine therapies to reduce inflammation and cartilage destruction in a rat joint instability model of OA, as measured by in vitro tests of activity and immunotoxicity, and in vivo tests of biodistribution, and disease-modifying effects. Outcome measures include gross and histological joint appearances, synovial fluid biomarkers, and measures of gait and pain perception. Project 3 represents the continuation of a clinical study to develop more effective physical and psychological interventions to reduce the pain, disability, and psychological distress experienced by overweight patients with persistent OA knee pain. The study evaluates the efficacy of new pain coping skills training and weight reduction protocols on pain, physical disability, and psychological distress using standardized outcome measures of OA pain and function (WOMAC, AIMS, OARSI criteria), biomechanical studies of pain and function, and biomarkers of inflammation and OA. Based on promising pilot study data, Project 4 will involve a randomized placebo controlled clinical trial of IL-1 receptor antagonist (IL-1Ra) for the prevention of pain and chondropathy following acute knee injury. Clinical outcomes will include standardized measures of injury related pain, function and chondropathy (KOOS, IKDC, and SFA score). The Program is supported by two Core facilities. Core A (Administrative Core) will coordinate the administration and research activities of the projects. Core B (Biomarker Core) will serve as a centralized facility for novel reagents, techniques, and training for quantitation of biomarkers of cartilage metabolism and inflammation in tissues and in fluids such as synovial fluid, serum, and tissue culture media. This strategy allows a mechanistic investigation of the overall theme of the project in a manner that can readily be translated from basic science experiments to clinical therapies and outcomes. The information gained from this Program Project will provide new insights into the development new pharmacologic, psychological, and physical therapies for the treatment of OA. [unreadable]